This invention relates to medicaments, particularly novel fused imidazolium derivatives useful for the treatment of cancers and novel synthetic intermediate compounds thereof.
As imidazolium derivatives fused with aryl or heteroaryl ring and having anti-tumor activity, only the 4,9-dioxonaphtho[2,3-d]imidazolium compounds (KP-1, KP-3 and the like) of the following formula have so far been disclosed in Khim. Pharm. Zh., 32(6), 10-11 (1998). 
(In the formula, Et and Me respectively represent ethyl and methyl, the same shall apply hereinafter.)
J. Med. Chem., 7(3), 362-364 (1964) discloses a compound having an antimicrobial action in which R1 and R2 of the general formula (I) of the present invention, which will be described later, are both lower alkyl, or one is -lower alkylene-(an aryl which may have one or more substituents) and the other is xe2x80x94CH3, xe2x80x94(CH2)3CH3 or -phenyl group, or one is -lower alkylene-COxe2x80x94 (an aryl which may have one or more substituents) and the other is xe2x80x94CH2CH(CH3)2 or xe2x80x94(CH2)3CH3, but there is no disclosure on its anti-tumor activity.
Also, 4,9-dioxonaphtho[2,3-d]imidazolium derivatives in which R1 and R2 of the general formula (I) of the present invention are both lower alkyl groups are disclosed in J. Org. Chem. USSR, 1, 1479-85 (1965), JP-A-3-258765 and JP-A-6-59371 and the like. However, there is no disclosure on the medicinal use of these compounds.
British Patent No. 1314881 discloses 1,4-dihydro-1,4-dioxonaphthalene derivatives useful as a herbicide, and JP-B-54-25085 discloses isoquinoline-5,8-dione derivatives useful as a herbicide, respectively. Also, several 1,4-dihydro-1,4-dioxonaphthalene derivatives are commonly known by Zh. Org. Khim., 22(8), 1736-42 (1986), J. Gen. Chem. USSR, 36, 649-652 (1966) and reagent catalogs [Sigma Aldrich Library of Rare Chemicals Structure Index, with update (Aldrich Chemical Company, Inc.) and the like]. However, all of these documents do not disclose on the medicinal use of these compounds.
Imidazole derivatives fused with aryl ring are disclosed in WO 97/30022, J. Med. Chem., 39(7), 1447-1451 (1996) and J. Med. Chem., 7(3), 362-364 (1964).
Creation of an anticancer agent which exhibits excellent anti-tumor activity and also has low toxicity is still in great demand.
The present inventors have conducted intensive studies on anticancer agents having less side effects and found as a result of the efforts that novel imidazolium derivatives fused with an aryl or heteroaryl ring, characterized by being substituted at the 1- and/or 3-position with substituted alkyl group etc., exhibit excellent anti-tumor activity and low toxicity, thus they can be useful as anticancer agents having wide margins of safety. In addition, by finding a 2-acylamino-3-amino-1,4-quinone derivative and a fused imidazole derivative useful as their synthetic intermediates and further finding that this synthetic intermediate 2-acylamino-3-amino-1,4-quinone derivative itself also shows low toxicity and excellent anti-tumor activity, the invention has been accomplished.
That is, the invention relates to a fused imidazolium derivative represented by the following general formula (I) and a pharmaceutical composition, particularly an anticancer agent, which comprises this fused imidazolium derivative and a pharmaceutically acceptable carrier. 
(Symbols in the formula have the following meanings;
R1 and R2: the same or different from each other and each represents -(lower alkyl having one or more substituents selected from group B), -(lower alkenyl having one or more substituents selected from group B), -(lower alkynyl having one or more substituents selected from group B), -RinD, -lower alkyl, -lower alkenyl or -lower alkynyl, with the proviso that at least one of R1 and R2 is -(lower alkyl having one or more substituents selected from group B), -(lower alkenyl having one or more substituents selected from group B), -(lower alkynyl having one or more substituents selected from group B), -(cycloalkyl having one or more substituents) or -(five- to seven-membered saturated heterocyclic ring which may have one or more substituents),
group B: xe2x80x94ORa, xe2x80x94SRa, -prodrug-formed OH, xe2x80x94O-lower alkylene-ORa, xe2x80x94O-lower alkylene xe2x80x94O-lower alkylene-ORa, xe2x80x94O-lower alkylene-NRaRb, xe2x80x94O-lower alkylene-O-lower alkylene-NRaRb, xe2x80x94O-lower alkylene-NRc-lower alkylene-NRaRb, xe2x80x94OCOxe2x80x94NRaRb, xe2x80x94SORa, xe2x80x94SO2Ra, xe2x80x94SO2NRaRb, xe2x80x94NRaxe2x80x94SO2Rb, xe2x80x94NRaRb, xe2x80x94NRc-lower alkylene-NRaRb, xe2x80x94N(-lower alkylene-NRaRb)2, -RinD, xe2x80x94NO2, xe2x80x94CN, -halogen, xe2x80x94CO2Ra, xe2x80x94COOxe2x88x92, xe2x80x94CONRaRb, xe2x80x94CONRaxe2x80x94Oxe2x80x94Rb, xe2x80x94NRaxe2x80x94CORb, xe2x80x94NRaxe2x80x94COxe2x80x94NRbRc, xe2x80x94OCORa and xe2x80x94COxe2x80x94Ra,
Ra, Rb and Rc: the same or different from one another and each represents xe2x80x94H, -lower alkyl, -lower alkylene-RinD or -RinD,
RinD: -(five- to seven-membered saturated heterocyclic ring which may have one or more substituents), -(cycloalkyl which may have one or more substituents), -(cycloalkenyl which may have one or more substituents), -(aryl which may have one or more substituents) or -(heteroaryl which may have one or more substituents),
R3: xe2x80x94H or -(lower alkyl which may have one or more substituents), or R2 and R3 may together form a lower alkylene having from 2 to 5 carbon atoms which may be interrupted with O, S or NR4 (R4: xe2x80x94H or -lower alkyl),
ring A: aryl ring which may have one or more substituents or heteroaryl ring which may have one or more substituents, and
Xxe2x88x92: counter anion, with the proviso that Xxe2x88x92 does not exist when the substituent xe2x80x94COOxe2x88x92 of the group B forms intramolecular salt with imidazolium cation,
with the proviso that compounds having the following combinations of R1and R2 are excluded:
(1) one is -lower alkylene-(aryl which may have one or more substituents) and the other is xe2x80x94CH3, xe2x80x94(CH2)3CH3 or -phenyl,
(2) one is -lower alkylene-CO-(aryl which may have one or more substituents) and the other is xe2x80x94CH2CH(CH3)2 or xe2x80x94(CH2)3CH3, or
(3) R1 and R2 are both -benzyl, xe2x80x94(CH2)2OC2H5 or xe2x80x94(CH2)2Oxe2x80x94COCH3; the same shall apply hereinafter.)
Also, the invention relates to a 2-acylamino-3-amino-1,4-quinone derivative represented by the following general formula (II) or a salt thereof, which is a synthetic intermediate of the above general formula (I) and has excellent anti-tumor activity by itself too, and to a pharmaceutical composition, particularly an anticancer agent, which contains this compound or a salt thereof and a pharmaceutically acceptable carrier. 
(Symbols in the formula have the following meanings;
R1 and R2: the same or different from each other and each represents -(lower alkyl having one or more substituents selected from group B), -(lower alkenyl having one or more substituents selected from group B), -(lower alkynyl having one or more substituents selected from group B), -RinD, -lower alkyl, -lower alkenyl or -lower alkynyl, with the proviso that at least one of R1 and R2 is -(lower alkyl having one or more substituents selected from group B), -(lower alkenyl having one or more substituents selected from group B), -(lower alkynyl having one or more substituents selected from group B), -(cycloalkyl having one or more substituents) or -(five- to seven-membered saturated heterocyclic ring which may have one or more substituents),
group B: xe2x80x94ORa, xe2x80x94SRa, -prodrug-formed OH, xe2x80x94O-lower alkylene-ORa, xe2x80x94O-lower alkylene-O-lower alkylene-ORa, xe2x80x94O-lower alkylene-NRaRb, xe2x80x94O-lower alkylene-O-lower alkylene-NRaRb, xe2x80x94O-lower alkylene-NRc-lower alkylene-NRaRb, xe2x80x94OCOxe2x80x94NRaRb, xe2x80x94SORa, xe2x80x94SO2Ra, xe2x80x94SO2NRaRb, xe2x80x94NRaxe2x80x94SO2Rb, xe2x80x94NRaRb, xe2x80x94NRc-lower alkylene-NRaRb, xe2x80x94N(-lower alkylene-NRaRb)2, -RinD, xe2x80x94NO2, xe2x80x94CN, -halogen, xe2x80x94CO2Ra, xe2x80x94CONRaRb, xe2x80x94CONRaRb, xe2x80x94CONRaxe2x80x94Oxe2x80x94Rb, xe2x80x94NRaxe2x80x94CORb, xe2x80x94NRaxe2x80x94COxe2x80x94NRbRc, xe2x80x94OCORa and xe2x80x94COxe2x80x94Ra,
Ra, Rb and Rc: the same or different from one another and each represents xe2x80x94H, -lower alkyl, -lower alkylene-RinD or -RinD,
RinD: -(five- to seven-membered saturated heterocyclic ring which may have one or more substituents), -(cycloalkyl which may have one or more substituents), -(cycloalkenyl which may have one or more substituents), -(aryl which may have one or more substituents) or -(heteroaryl which may have one or more substituents),
R3: xe2x80x94H or -(lower alkyl which may have one or more substituents), or R2 and R3 may together form a lower alkylene having from 2 to 5 carbon atoms which may be interrupted with O, S or NR4 (R4: xe2x80x94H or -lower alkyl), and
ring A: aryl ring which may have one or more substituents or heteroaryl ring which may have one or more substituents,
with the proviso that compounds of the following table are excluded;
(in this table, Comp means compound number, Me means methyl group, Et means ethyl group and Ph means phenyl group, and in the case of a substituted phenyl group, the substituent is shown before Ph together with the substituting position, e.g., 3,4-Clxe2x80x94Ph represents 3,4-dichlorophenyl, the same shall apply hereinafter).
The compounds shown in Table 2 are commonly known by British Patent No. 1314881 and JP-B-54-25085 in relation to herbicides, Zh. Org. Khim., 22(8), 1736-42 (1986) and J. Gen. Chem. USSR, 36, 649-652 (1966) in relation to their synthesis methods, and by reagent catalogs [Sigma Aldrich Library of Rare Chemicals Structure Index, with update (Aldrich Chemical Company, Inc.) and the like].)
In addition, the invention relates to a fused imidazole derivative represented by the following general formula (III) or a salt thereof, which is a novel synthetic intermediate of the aforementioned general formula (I). 
(Symbols in the formula have the following meanings;
R1: -(lower alkyl having one or more substituents selected from group B), -(lower alkenyl having one or more substituents selected from group B), -(lower alkynyl having one or more substituents selected from group B) or -(cycloalkyl having one or more substituents), with the proviso that a lower alkyl group having one or more substituents selected from the group consisting of xe2x80x94NH2, xe2x80x94NMe2, xe2x80x94NEt2, xe2x80x94OH, -halogen and -(phenyl which may be substituted by xe2x80x94Cl, xe2x80x94F, xe2x80x94Me or xe2x80x94OMe) is excluded,
group B: xe2x80x94ORa, xe2x80x94SRa, -prodrug-formed OH, xe2x80x94O-lower alkylene-ORa, xe2x80x94O-lower alkylene-O-lower alkylene-ORa, xe2x80x94O-lower alkylene-NRaRb, xe2x80x94O-lower alkylene-O-lower alkylene-NRaRb, xe2x80x94O-lower alkylene-NRc-lower alkylene-NRaRb, xe2x80x94OCOxe2x80x94NRaRb, xe2x80x94SORa, xe2x80x94SO2Ra, xe2x80x94SO2NRaRb, xe2x80x94NRaxe2x80x94SO2Rb, xe2x80x94NRaRb, xe2x80x94NRc-lower alkylene-NRaRb, xe2x80x94N(-lower alkylene-NRaRb)2, -RinD, xe2x80x94NO2, xe2x80x94CN, -halogen, xe2x80x94CO2Ra, xe2x80x94CONRaRb, xe2x80x94CONRaxe2x80x94Oxe2x80x94Rb, xe2x80x94NRaxe2x80x94CORb, xe2x80x94NRaxe2x80x94COxe2x80x94NRbRc, xe2x80x94OCORa and xe2x80x94COxe2x80x94Ra,
Ra, Rb and Rc: the same or different from one another and each represents xe2x80x94H, -lower alkyl, -lower alkylene-RinD or -RinD,
RinD: -(five- to seven-membered saturated heterocyclic ring which may have one or more substituents), -(cycloalkyl which may have one or more substituents), -(cycloalkenyl which may have one or more substituents), -(aryl which may have one or more substituents) or -(heteroaryl which may have one or more substituents),
R3: xe2x80x94H or -(lower alkyl which may have one or more substituents), and
ring A: aryl ring which may have one or more substituents or heteroaryl ring which may have one or more substituents, the same shall apply hereinafter.)
The compounds of general formula (I), (II) and (III) are further described.
According to this description, the term xe2x80x9clowerxe2x80x9d means a straight or branched form of hydrocarbon chain having from 1 to 6 carbon atoms. As the xe2x80x9clower alkylxe2x80x9d, it is preferably an alkyl group having from 1 to 4 carbon atoms, and its particularly preferred examples include methyl, ethyl, n-propyl, isopropyl, n-butyl and isobutyl groups. As the xe2x80x9clower alkenylxe2x80x9d, its preferred examples include vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl and 3-butenyl groups. As the xe2x80x9clower alkynylxe2x80x9d, its preferred examples include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl and 1-methyl-2-propynyl groups. Also, as the xe2x80x9clower alkylenexe2x80x9d, its preferred examples include methylene, ethylene, trimethylene and 2,2-dimethyltrimethylene groups.
The xe2x80x9carylxe2x80x9d means an aromatic hydrocarbon ring group, and its preferred examples include aryl groups having from 6 to 14 carbon atoms, more preferably phenyl, naphthyl and fluorenyl groups. Also, as the xe2x80x9caryl ringxe2x80x9d in the ring A, it is a ring which forms the above aryl ring, and its preferred examples include benzene and naphthalene rings.
Examples of the xe2x80x9cheteroarylxe2x80x9d include five- or six-membered monocyclic heteroaryl groups containing from 1 to 4 hetero atoms selected from N, S and O and bicyclic heteroaryl groups in which they are fused with a benzene ring or five- or six-membered monocyclic heteroaryl ring, which may be partially saturated. Also, when it contains N atom, it may form N-oxide. In this case, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and triazinyl groups are preferred as the five- or six-membered monocyclic heteroaryl, and benzofuranyl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzoxazolyl, benzoxadiazolyl, benzoimidazolyl, indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, benzodioxolyl, indolizinyl and imidazopyridyl groups are preferred as the bicyclic heteroaryl. As the partially saturated heteroaryl, 1,2,3,4-tetrahydroquinolyl group and the like can be exemplified. Further preferred are furyl, thienyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridadinyl, indolyl, benzoimidazolyl, benzodioxonyl and quinolyl groups, and particularly preferred are pyridyl, pyrazinyl and pyrimidinyl groups.
The heteroaryl ring of the ring A is a ring which forms the above heteroaryl group, preferably a five- or six-membered monocyclic heteroaryl ring, and more preferred are thiophene, furan, pyrrole, imidazole, oxazole, thiazole, pyridine, pyrazine and pyrimidine rings.
As the xe2x80x9ccycloalkylxe2x80x9d, preferred are cycloalkyl groups having from 3 to 10 carbon atoms and particularly preferred are cyclopropyl, cyclopentyl, cyclohexyl and adamantyl groups. As the xe2x80x9ccycloalkenylxe2x80x9d, preferred are cycloalkenyl groups having from 3 to 8 carbon atoms and particularly preferred are cyclopentenyl and cyclohexenyl groups.
As the xe2x80x9ccounter anionxe2x80x9d, there is no particular limitation with the proviso that it is a pharmaceutically acceptable anion as a counter anion of imidazolium cation, and its preferred examples include monovalent or divalent anions such as halogen ions, organic sulfonate ions (methanesulfonate ion, ethanesulfonate ion, benzenesulfonate ion, toluenesulfonate ion and the like), acetate ion, trifluoroacetate ion, carbonate ion, sulfate ion and the like, of which halogen ions are particularly preferred.
As the xe2x80x9chalogenxe2x80x9d, F, Cl, Br and I atoms can be exemplified, and the xe2x80x9chalogen ionxe2x80x9d means their ions. The xe2x80x9chalogeno lower alkylxe2x80x9d is the aforementioned lower alkyl which is substituted by one or more of the halogen, and is preferably xe2x80x94CF3.
The xe2x80x9cfive- to seven-membered saturated heterocyclic ringxe2x80x9d is a five- to seven-membered monocyclic saturated heterocyclic ring containing from 1 to 4 hetero atoms selected from N, S and O, or its cross-linked ring. Preferred are tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, piperazinyl, azepanyl, diazepanyl, quinuclidinyl, piperidyl and morpholinyl groups.
The xe2x80x9c-prodrug-formed OHxe2x80x9d is a group which formed a reversible prodrug derivative that can be restored to its parent compound (original hydroxy compound) in the living body, and its examples include groups described, e.g., in Prog. Med., 5: 2157-2161 (1985). Its preferred examples include xe2x80x94OCO-(lower alkylene which may have one or more substituents)-COOR (R represents H or lower alkyl, the same shall apply hereinafter), xe2x80x94OCO-(lower alkenylene which may have one or more substituents)-COOR, xe2x80x94OCO-(aryl which may have one or more substituents), xe2x80x94OCO-lower alkylene-o-lower alkylene-COOR, xe2x80x94OCOxe2x80x94COxe2x80x94R, xe2x80x94OCO-(lower alkyl which may have one or more substituents), xe2x80x94OSO2-(lower alkylene which may have one or more substituents)-COOR, xe2x80x94O-phthalidyl, 5-methyl-1,3-dioxolen-2-one-4-yl-methyloxy and the like.
As the substituent in the -(five- to seven-membered saturated heterocyclic ring which may have one or more substituents), -(cycloalkyl which may have one or more substituents), -(cycloalkyl which has one or more substituents), -(cycloalkenyl which may have one or more substituents), -(aryl which may have one or more substituents) or -(heteroaryl which may have one or more substituents), it is not particularly limited but is preferably from 1 to 4 substituents selected from the following group C.
Group C: -lower alkyl, -halogen, -halogeno lower alkyl, xe2x80x94ORa, xe2x80x94O-lower alkylene-ORa, xe2x80x94SRa, xe2x80x94NRaRb, xe2x80x94NO2, xe2x80x94CN, xe2x80x94CO2Ra, xe2x80x94COxe2x80x94NRaRb, xe2x80x94CORa, xe2x80x94NRaxe2x80x94CORb, xe2x80x94SO2NRaRb, -lower alkylene-NRaRb, -aryl, -lower alkylene-aryl and xe2x80x94OCOxe2x80x94Ra (in these formulae, Ra and Rb are as defined in the foregoing).
Among the group C, more preferred are -lower alkyl, -halogen, -halogeno lower alkyl, xe2x80x94OH, xe2x80x94O-lower alkyl, xe2x80x94O-lower alkylene-OH, xe2x80x94O-lower alkylene-O-lower alkyl, -lower alkylene-NH2, xe2x80x94NH2, xe2x80x94NH-lower alkyl, xe2x80x94N (lower alkyl)2, xe2x80x94CO2H, xe2x80x94CO2-lower alkyl, xe2x80x94COxe2x80x94NH2, xe2x80x94SO2xe2x80x94NH2, xe2x80x94NO2 and xe2x80x94CN. The same shall apply hereinafter.
As the substituent of the xe2x80x9caryl ring which may have one or more substituentsxe2x80x9d or xe2x80x9cheteroaryl ring which may have one or more substituentsxe2x80x9d in the ring A, the aforementioned groups of the group C can be cited as preferred examples, and more preferred groups are also the same as described above. Particularly preferred is xe2x80x94NO2.
Though the substituent the xe2x80x9clower alkyl which may have one or more substituentsxe2x80x9d of R3 is not particularly limited, it is preferably a substituent of the aforementioned group B, more preferably -halogen, xe2x80x94ORa, xe2x80x94SRa, xe2x80x94NRaRb, xe2x80x94NO2 or xe2x80x94CN.
In this connection, as the groups shown using Ra, Rb and Rc in the aforementioned group B and group C, groups in which Ra, Rb and Rc are xe2x80x94H or -lower alkyl are more desirable.
In general formula (I), the term xe2x80x9cR2 and R3 together form a lower alkylene having from 2 to 5 carbon atoms which may be interrupted with O, S or NR4 (R4: xe2x80x94H or -lower alkyl)xe2x80x9d means that R2 and R3 together form a lower alkylene chain which may be interrupted with O, S or NR4 (preferably xe2x80x94(CH2)4xe2x80x94, xe2x80x94(CH2)2OCH2xe2x80x94 or xe2x80x94(CH2)2N(Me)CH2xe2x80x94), and combined with the adjacent N and C atoms to form a four- to seven-membered hetero ring which is fused with imidazole ring.
Preferred compound of the compound (I) or (II) of the invention is,
(1) a compound in which at least one of R1 and R2 is -(lower alkyl having one or more substituents selected from the group B), -(lower alkenyl having one or more substituents selected from the group B), -(lower alkynyl having one or more substituents selected from the group B), -(cycloalkyl having one or more substituents selected from the group C) or -(five- to seven-membered saturated heterocyclic ring which may have one or more substituents selected from the group C); RinD is -(five- to seven-membered saturated heterocyclic ring which may have one or more substituents selected from the group C), -(cycloalkyl which may have one or more substituents selected from the group C), -(cycloalkenyl which may have one or more substituents selected from the group C), -(aryl which may have one or more substituents selected from the group C) or -(heteroaryl which may have one or more substituents selected from the group C); R3 is xe2x80x94H or -(lower alkyl which may have one or more substituents selected from the group B), or R2 and R3 may together form a lower alkylene having from 2 to 5 carbon atoms which may be interrupted with O, S or NR4 (R4: xe2x80x94H or -lower alkyl); and ring A is aryl ring which may have one or more substituents selected from the group C or heteroaryl ring which may have one or more substituents selected from the group C,
(2) a compound in which at least one of R1and R2 is a lower alkyl having one or more substituents selected from the group B,
(3) a compound in which both of R1 and R2 are the same or different lower alkyl having one or more substituents selected from the group B,
(4) a compound in which at least one of R1 and R2 is a lower alkyl having one or more substituents selected from the group consisting of xe2x80x94ORa, xe2x80x94NRaRb, xe2x80x94NRaxe2x80x94CORb, xe2x80x94O-lower alkylene-ORa, xe2x80x94O-lower alkylene-O-lower alkylene-ORa, xe2x80x94SRa, xe2x80x94CONRaRb, xe2x80x94CN, -(cycloalkyl which may have one or more substituents selected from the group C), -(five- to seven-membered saturated heterocyclic ring which may have one or more substituents selected from the group C), -(aryl which may have one or more substituents selected from the group C) and -(heteroaryl which may have one or more substituents selected from the group C),
(5) a compound in which at least one of R1and R2 is a lower alkyl having one or more substituents selected from the group consisting of xe2x80x94ORa, xe2x80x94O-lower alkylene-ORa, xe2x80x94O-lower alkylene-O-lower alkylene-ORa, -(five- to seven-membered saturated heterocyclic ring which may have one or more substituents selected from the group C), -(aryl which may have one or more substituents selected from the group C) and -(heteroaryl which may have one or more substituents selected from the group C),
(6) a compound in which at least one of R1and R2 is a lower alkyl substituted by a heteroaryl group selected from furyl, thienyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolyl, benzoimidazolyl, benzodioxonyl and quinolyl group, which may have one or more substituents selected from the group C,
(7) a compound in which one of R1 and R2 is a lower alkyl substituted by xe2x80x94O-lower alkyl and the other is a lower alkyl substituted by one substituent selected from the group consisting of xe2x80x94O-lower alkylene-O-lower alkyl, xe2x80x94O-lower alkylene-O-lower alkylene-O-lower alkyl, -(aryl which may have one or more substituents selected from the group C), -(heteroaryl which may have one or more substituents selected from the group C) and xe2x80x94O-lower alkyl,
(8) a compound in which at least one of R1 and R2 is a lower alkyl having one substituent selected from the group consisting of -(heteroaryl selected from pyridyl, pyrazinyl and pyrimidinyl, which may have one or more substituents selected from the group C), xe2x80x94O-lower alkylene-O-lower alkyl and xe2x80x94O-lower alkyl,
(9) a compound in which R3 is methyl group,
(10) a compound in which the ring A is benzene ring which may have one or more substituents selected from the group C or a heteroaryl ring selected from thiophene, furan, pyrrole, imidazole, oxazole, thiazole, pyridine, pyrazine, pyridazine and pyrimidine ring, which may have one or more substituents selected from the group C,
(11) a compound in which the ring A is benzene ring which may be substituted by xe2x80x94NO2, or
(12) a compound in which Xxe2x88x92 is a halogen ion.
Also, another preferred compound of the compound (I) of the invention is a fused imidazolium derivative in which R1 and R2 are the same or different from each other and each represents -(lower alkyl having one or more substituents selected from group Bxe2x80x2), -(lower alkenyl having one or more substituents selected from group Bxe2x80x2), -(lower alkynyl having one or more substituents selected from group Bxe2x80x2), -(cycloalkyl which may have one or more substituents selected from group Cxe2x80x2), -(five- or six-membered monocyclic heteroaryl which may have one or more substituents selected from group Cxe2x80x2), -(aryl which may have one or more substituents selected from group Cxe2x80x2), -(five- to seven-membered saturated heterocyclic ring which may have one or more substituents selected from group Cxe2x80x2), -lower alkylene-(aryl which may have one or more substituents selected from group Cxe2x80x2), -lower alkylene-CO-(aryl which may have one or more substituents selected from group Cxe2x80x2), -lower alkyl, -lower alkenyl or -lower alkynyl, with the proviso that at least one of R1 and R2 is -(lower alkyl having one or more substituents selected from group Bxe2x80x2). -(lower alkenyl having one or more substituents selected from group Bxe2x80x2) or -(lower alkynyl having one or more substituents selected from group Bxe2x80x2); group Bxe2x80x2is xe2x80x94ORa, xe2x80x94SRa, -prodrug-formed OH, xe2x80x94O-lower alkylene-RinD, xe2x80x94SORa, xe2x80x94SO2Ra, xe2x80x94SO2NRaRb, xe2x80x94NRaxe2x80x94SO2Rb, xe2x80x94NRaRb, xe2x80x94NRc-lower alkylene-RinD, xe2x80x94N(-lower alkylene-RinD)2, xe2x80x94NRc-lower alkylene-NRaRb, xe2x80x94N(lower alkylene-NRaRb)2, -(five- to seven-membered saturated heterocyclic ring which may have one or more substituents selected from group Cxe2x80x2), -(five- or six-membered monocyclic heteroaryl which may have one or more substituents selected from group Cxe2x80x2), -cycloalkyl, xe2x80x94S-lower alkylene-RinD, xe2x80x94NO2, xe2x80x94CN, xe2x80x94CO2Ra, xe2x80x94CONRaRb, xe2x80x94NRaxe2x80x94CORb, xe2x80x94OCORa, xe2x80x94CO-lower alkyl and xe2x80x94CO-(five- or six-membered monocyclic heteroaryl which may have one or more substituents selected from group Cxe2x80x2); Ra, Rband Rc are the same or different from one another and each represents xe2x80x94H, -lower alkyl or -RinD; RinD is -(five- to seven-membered saturated heterocyclic ring which may have one or more substituents selected from group Cxe2x80x2), -(aryl which may have one or more substituents selected from group Cxe2x80x2) or -(five- or 6-membered monocyclic heteroaryl which may have one or more substituents selected from group Cxe2x80x2); group Cxe2x80x2is -lower alkyl, -halogen, xe2x80x94ORa, xe2x80x94SRa, xe2x80x94NRaRb, xe2x80x94NO2, xe2x80x94CN, xe2x80x94CO2Ra, xe2x80x94COxe2x80x94NRaRb, xe2x80x94CORa, xe2x80x94NRaxe2x80x94CORb, and xe2x80x94OCOxe2x80x94Ra; R3 is xe2x80x94H or -lower alkyl; ring A is benzene ring which may have a substituent selected from the group consisting of -lower alkyl, xe2x80x94ORa, xe2x80x94NRaRb, xe2x80x94CN, -halogen and xe2x80x94NO2; and Xxe2x88x92 is counter anion.
Among compounds (I) of the invention, particularly preferred compounds are 1-[(6-chloro-3-pyridyl)methyl]-3-(2-methoxyethyl)-2-methyl-4,9-dioxo-4,9-dihydro-1H-naphtho[2,3-d]imidazol-3-ium, 1,2-dimethyl-4,9-dioxo-3-[(2-tetrahydrofuranyl)methyl]-4,9-dihydro-1H-naphtho[2,3-d]imidazol-3-ium, 1,3-bis(2-methoxyethyl)-2-methyl-4,9-dioxo-4,9-dihydro-1H-naphtho[2,3-d]imidazol-3-ium, 3-(2-methoxyethyl)-2-methyl-4,9-dioxo-1-(2-pyrazinylmethyl)-4,9-dihydro-1H-naphtho[2,3-d]imidazol-3-ium, 1-[3-(1H-4-imidazolyl)propyl]-3-(2-methoxyethyl)-2-methyl-4,9-dioxo-4,9-dihydro-1H-naphtho[2,3-d]imidazol-3-ium, 3-(2-methoxyethyl)-2-methyl-1-[(5-methyl-2-pyrazinyl)methyl]-4,9-dioxo-4,9-dihydro-1H-naphtho[2,3-d]imidazol-3-ium, 2-methyl-4,9-dioxo-1,3-bis(2-pyrazinylmethyl)-4,9-dihydro-1H-naphtho[2,3-d]imidazol-3-ium, 1-[2-(2-methoxyethoxy)ethyl]-3-(2-methoxyethyl)-2-methyl-4,9-dioxo-4,9-dihydro-1H-naphtho[2,3-d]imidazol-3-ium, 1-{2-[2-(2-methoxyethoxy)ethoxy]ethyl}-3-(2-methoxyethyl)-2-methyl-4,9-dioxo-4,19-dihydro-1H-naphtho[2,3-d]imidazol-3-ium, 1-(2-methoxyethyl)-2-methyl-4,9-dioxo-3-(3-pyridylmethyl)-4,9-dihydro-1H-naphtho[2,3-d]imidazol-3-ium, 3-(2-methoxyethyl)-2-methyl-4,9-dioxo-1-(2-pyridylmethyl)-4,9-dihydro-1H-naphtho[2,3-d]imidazol-3-ium, 3-(2-methoxyethyl)-2-methyl-4,9-dioxo-1-(4-pyridylmethyl)-4,9-dihydro-1H-naphtho[2,3-d]imidazol-3-ium, 1-[(2-chloro-3-pyridyl)methyl]-3-(2-methoxyethyl)-2-methyl-4,9-dioxo-4,9-dihydro-1H-naphtho[2,3-d]imidazol-3-ium, 1-[(2-hydroxy-4-pyridyl)methyl]-3-(2-methoxyethyl)-2-methyl-4,9-dioxo-4,9-dihydro-1H-naphtho[2,3-d]imidazol-3-ium, 3-(2-methoxyethyl)-1-[(6-methoxy-3-pyridyl)methyl]-2-methyl-4,9-dioxo-4,9-dihydro-1H-naphtho[2,3-d]imidazol-3-ium, 1-[(2-chloro-4-pyridyl)methyl]-3-(2-methoxyethyl)-2-methyl-4,9-dioxo-4,9-dihydro-1H-naphtho[2,3-d]imidazol-3-ium, 1-(4-chlorobenzyl)-3-(2-methoxyethyl)-2-methyl-4,9-dioxo-4,9-dihydro-1H-naphtho[2,3-d]imidazol-3-ium, 1-(4-fluorobenzyl)-3-(2-methoxyethyl)-2-methyl-4,9-dioxo-4,9-dihydro-1H-naphtho[2,3-d]imidazol-3-ium and 1,3-bis(2-methoxyethyl)-2-methyl-5-nitro-4,9-dioxo-4,9-dihydro-1H-naphtho[2,3-d]imidazol-3-ium, or tautomers thereof and their salts with halogen ions.
The compound (I) of the invention exists in tautomer forms represented by the following formula due to delocalization of the cation, and these isomers in separated forms or mixtures thereof are included in the invention. The compound mentioned herein as 1H-imidazol-3-ium derivative includes 3H-imidazol-1-ium derivative as its tautomer and mixture of both isomers. In this connection, Xxe2x88x92 does not exist when the compound (I) has a substituent xe2x80x94COOxe2x88x92 and forms intramolecular salt with the imidazolium cation. 
In addition to the aforementioned salt with a counter anion, the compound (I) of the invention forms other salts in some cases depending on the kinds of substituents, and these salts are also included in the invention. In addition, the compound (II) or (III) of the invention also forms salts in some cases depending on the kinds of substituents, and these salts are also included in the invention. Though these salts are not particularly limited with the proviso that they are pharmaceutically acceptable salts, acid addition salts with an inorganic acid (hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid and the like) and with an organic acid (formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, aspartic acid, glutamic acid and the like) can be cited as illustrative examples of acid addition salts, and salts with an inorganic base containing a metal (sodium, potassium, magnesium, calcium, aluminum and the like) or with an organic base (methylamine, ethylamine, ethanolamine, lysine, ornithine and the like) and ammonium salts and the like can be exemplified as salts with bases.
Depending on the kinds of substituents, geometrical isomers and tautomers exist in the compound (I), (II) or (III) of the invention in some cases, and these isomers in separated forms or mixture thereof are included in the invention. Also, since certain compounds of the invention have asymmetric carbon atom, isomers based on the asymmetric carbon atom can exist. The invention includes mixed and separated forms of these optical isomers. Also, compounds of the invention may sometimes form N-oxide depending on the kinds of substituents, and these N-oxide compounds are also included in the invention. In addition, various hydrates and solvates and polymorphic substances of the compound (I), (II) or (III) of the invention are also included in the invention.
Synthesis Methods
The compounds (I), (II) and (III) of the invention can be synthesized easily by using similar methods described in references, e.g., J. Org. Chem. USSR, 1, 1479-85 (1965), J. Med. Chem., 7(3), 362-364 (1964), JP-A-3-258765, or by applying the methods known to those skilled in the art.
In this connection, depending on the kind of functional group, it may sometimes be effective from the viewpoint of synthesis techniques to replace the functional group with an appropriate protecting group, namely a group which can be easily converted into the functional group, at the stage of starting materials or synthetic intermediates. Thereafter, a desired compound can be obtained by removing the protecting group as occasion demands. Examples of such functional groups include a amino group, a hydroxyl group, a carboxyl group and the like and examples of their protecting groups include those which are described in xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, 2nd edition, edited by Greene and Wuts, which may be optionally used depending on the reaction conditions.
The following describes typical Synthesis methods. 
(In the formula, Rxe2x80x2 means hydrogen, methoxy or halogen group, and Hxe2x80x94X means an acid which forms anion (preferably hydrogen fluoride, hydrogen chloride, hydrogen bromide, hydrogen iodide, methanesulfonic acid, ethanesulfonic acid and the like). The same shall apply hereinafter.)
Synthesis Method 1
The compound (II) of the invention can be synthesized in the usual procedures by allowing a compound (IV) to react with amines (V). For example, it can be synthesized by applying the methods described in Chem. Pharm. Bull., 44(6), 1181-1187 (1996), Syn. Comm., 27 (12), 2143-2157 (1997), Tetrahedron. Lett., 39(42), 7677-7678 (1998) and the like, and it is advantageous to carry out the reaction at ambient temperature or under heating in an appropriate inert solvent (benzene and the like) using reaction equivalent amounts of the compounds (IV) and (V), or one of them in an excess amount, if necessary using an appropriate inorganic base (potassium carbonate and the like) or organic base (triethylamine and the like) as an acid capturing agent.
Synthesis Method 2
The compound (I) of the invention can be synthesized in the usual procedures by subjecting the compound (II) of the invention to cyclization and making it into a quaternary salt. For example, the reaction can be carried out by applying the method described in J. Org. Chem. USSR, 1, 1479-85 (1965), and it is advantageous to carry out the reaction at ambient temperature or under heating in an appropriate inert solvent (e.g., an alcohol solvent) using a reaction equivalent amount or an excess amount of an acid.
Synthesis Method 3
(In the formula, Rd and Re are any groups defined in R1and R2. The same shall apply hereinafter.)
Two compounds (IIa) and (IIb) of the invention can be synthesized by hydrolysis of the compound (I) of the invention in the usual procedures. The obtained compounds can also be made into synthetic intermediates of desired compound (I) of the invention by subjecting them to commonly known substituent-modification reactions.
The hydrolysis reaction can be carried out by applying the method described in J. Med. Chem., 7(3), 362-364 (1964) and the like, and it is advantageous to carry out the reaction at ambient temperature or under heating in an appropriate inert solvent (ethanol and the like) using a reaction equivalent amount or an excess amount of a base. As the base, lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate can be exemplified.
Synthesis Method 4
The compound (III) of the invention can be synthesized in accordance with the method described in J. Med. Chem., 39(7), 1447-1451 (1996) and the like, by subjecting a compound (VI) to cyclization reaction in the presence of a base such as sodium hydroxide and the like.
Synthesis Method 5
The compound (I) of the invention can be synthesized by allowing the compound (III) of the invention to react with a halide (VII) to make it into a quaternary salt For example, the reaction can be carried out in accordance with the method described in J. Med. Chem., 7(3), 362-364 (1964), preferably in an appropriate inert solvent using reaction equivalent amounts of the compounds (III) and (VII), or one of them in an excess amount, at ambient temperature or under heating, preferably under reflux temperature of the solvent.
In addition to the above Synthesis methods, compounds of the invention can also be synthesized by various commonly known modification methods of substituents. For example, a compound having a substituent containing sulfonyl bond can be synthesized from a compound having sulfide bond or sulfinyl bond by usual oxidation reaction. A N-oxide derivative of a compound having a N atom-containing heteroaryl group (e.g., pyridyl group) as a substituent can be synthesized by usual oxidation reaction. A compound having a carboxylic acid-containing substituent can be synthesized from a compound having ester or amide bond by usual hydrolysis reaction. A compound having an aminoalkyl group-containing substituent can be synthesized from a compound having a halogen-substituted alkyl bond by usual amination reaction. In case that the compounds (II) and (III) of the invention are in free forms, they can be made into salts by usual salt forming reaction as occasion demands.
Synthesis of Material Compounds
Some of the material compounds of the compounds of the invention are novel compounds, and these compounds can be synthesized easily in a similar manner as known material compounds or by using methods commonly known to those skilled in the art. Typical synthesis methods are shown below. 
The compound (IV) can be synthesized in accordance with the method described in J. Org. Chem. USSR, 1, 1479-85 (1965) and the like, by a usual acylation reaction in which a compound (VIII) is allowed to react with a reactive carboxylic acid derivative such as an acid halide, acid anhydride and the like. 
(In the formula, B1 represents pyridine ring which may have one or more substituents. The same shall apply hereinafter.)
An aminomethylpyridine derivative (X) can be synthesized by the reduction of a compound (IX) in accordance with the method described in German Patent No. 3726993 (1989) and the like. 
The compound (VI) can be synthesized by the amination of a compound (XI) in accordance with the method described in J. Med. Chem., 39(7), 1447-1451 (1996) and the like. 
The compound (VIII) can be synthesized by the amination of a compound (XII) in accordance with the method described in J. Het. Chem., 33(1), 113-117 (1996), Syn. Comm., 27(12), 2143-2157 (1997), Tetrahedron. Lett., 39(42), 7677-7678 (1998) and the like. 
The compound (IV) can be synthesized by the amidation of the compound (XII). It is advantageous to carry out the reaction by activating a reaction equivalent amount of a compound (XIII) using an appropriate inorganic base (NaH and the like) or organic base (NaOMe and the like) in an appropriate inert solvent (N,N-dimethylformamide (DMF) and the like) and then allowing it to react with a reaction equivalent amount or an excess amount of the compound (XII) at ambient temperature or under heating.
Isolation and purification of the compounds of the invention synthesized in the above described manner are carried out by applying general chemical techniques such as extraction, concentration, evaporation, crystallization, filtration, recrystallization, various types of chromatography and the like.
Each form of isomers can be isolated by usual procedures making use of physicochemical differences among isomers. For example, racemic compounds can be converted into optically pure isomers by a conventional optical resolution method [e.g., a method in which they are made into diastereomer salts with a general optically active acid (tartaric acid and the like) and then subjected to optical resolution]. Also, a diastereomer mixture can be separated by fractional crystallization, chromatography and the like. In addition, an optically active compound can also be synthesized by using an appropriate optically active material.
Industrial Applicability
The compounds (I) and (II) of the invention are useful as anticancer agents which have excellent cancer cell growth inhibitory activity, low toxicity and wide margins of safety. Accordingly, the compounds of the invention have the inhibitory activity on growth of tumors, preferably all solid tumors and lymphomas, particularly skin cancer, bladder cancer, breast cancer, uterine cancer, ovary cancer, prostate cancer, lung cancer, colon cancer, pancreas cancer, renal cancer, gastric cancer and the like, thus they are useful for the treatment thereof. Particularly, they show excellent anti-tumor activity for many kinds of tumor types in a cancer cell growth inhibition test and an in vivo tumor growth inhibition test using a mouse tumor xenograft model, and the activity is superior to those of some existing anticancer agents. Accordingly, they are expected as therapeutic agents for tumor types which show resistance against existing anticancer agents.
Effects of the compounds of the invention were verified by the following tests.